IL-17 family cytokines such as IL-17 (aka IL-17A), the closely related IL-17F, and IL-25 have been implicated in the pathogenesis of various inflammatory and auto-immune diseases. In order to devise strategies to disable signaling by these cytokines in diseases, it is imperative to understand the pathways and molecular mechanisms by which these cytokines transmit signals in target cells to effect gene expression. In the past we have cloned an adaptor protein (CIKS) that is absolutely required for signaling by IL-17 family cytokines. In FY 2011 we have made use of a previously generated library of mutant versions of this adaptor to identify critical signaling domains of CIKS. To this end we reconstituted CIKS-deficient primary mouse embryo fibroblasts with wild-type and mutant CIKS proteins via lentiviral transduction and assayed responses to IL-17 signaling. In this way we identified an N-terminal domain of the CIKS adaptor that is absolutely required for interaction with TRAF6 and, in consequence, activation of NF-kB transcription factors. In FY 2011 we also determined that NF-kB plays a prominent role in the transcriptional response to IL-17 cytokine signaling. Finally we provided a proof-of-principle for the idea that the protein-protein interaction motifs on the CIKS adaptor protein can be a target for therapeutic intervention. Specifically we demonstrated that cell-penetrating decoy peptides that are based on the small TRAF6 interaction domain of CIKS successfully interfered with IL-17 induced activation of NF-kB and downstream gene transcription that depends on this transcription factor. Ultimately small molecule inhibitors could be developed based on decoy peptides that strongly interfere with CIKS-mediated signaling and thus IL-17 cytokine signaling in diseases in which these cytokines critically contribute to pathology.